Project Summary/Abstract Cocaine use disorder (CUD) continues to be a major public health and social problem in the United States. A hallmark of CUD is individual differences in vulnerability, relapse and treatment efficacy. Our overall goal is to achieve a better understanding of individual differences in the long-term consequences of the reinforcing effects of cocaine using a unique nonhuman primate model of CUD. We propose to use neuronal-derived exosomes (NDE) in the blood to identify molecular biomarkers associated with an individual's vulnerability to cocaine abuse, susceptibility to relapse following abstinence, and success or failure of targeted therapies for cocaine abuse. Exosomes are nano-vesicles that are released by all cell types. Those released by cells under stressed or pathologic states are different from those released under normal physiologic conditions. Taking advantage of this difference, several exosome-based diagnostic and prognostic biomarkers have been successfully developed. Recent studies have also shown that exosomes in biofluids can be used to establish molecular signatures associated with methamphetamine, heroin, and alcohol abuse. However, exosomes have not been used to understand cocaine abuse ? the focus of this application. The proposed study capitalizes on a timely opportunity to use plasma samples from an ongoing NIDA-funded study (R01 DA017763-11; PI: Nader) to understand cocaine abuse in socially housed female and male monkeys. The parent study is testing the efficacy of several pharmacological agents thought to work differently in dominant and subordinate female and male monkeys. All monkeys (socially housed and naturally forming dominant and subordinate hierarchies) are undergoing comprehensive behavioral and cognitive testing, and neuroimaging of central dopamine D2/D3 receptor (D2/D3R) availability using positron emission tomography (PET) imaging. With the costs of key measures covered by existing funding, the availability of plasma samples from these monkeys offers a valuable and cost-effective opportunity to advance our understanding of how exosomes could provide a non- invasive molecular tool to inform us about cocaine abuse and treatment outcomes. Pilot and feasibility data (a) validate our ability to isolate and characterize NDEs from stored plasma samples, and (b) support the utility of NDE biomarkers to understand the molecular effects of cocaine self-administration (SA), and effects of social ranking on cocaine vulnerability and treatment outcomes in male and female monkeys. Thus, we propose two Specific Aims: I. To characterize NDEs associated with cocaine SA in socially housed male and female monkeys. II. To characterize NDEs associated with success or failure of pharmacological agents to decrease cocaine SA in socially housed male and female monkeys. Our results will significantly advance progress toward characterization of non-invasive biomarkers for molecular understanding of cocaine abuse vulnerability and relapse, and contribute in developing a personalized-medicine strategy for treating drug abuse.